Delayed release oral dosage forms for treatment of intestinal disorders

ABSTRACT

An orally administrable pharmaceutical dosage form for selectively administering a drug to the intestine comprises a plurality of enteric coated granules of the drug contained in an enterically coated capsule which releases the granules in the small intestine. The granules are preferably coated with a coating which remains intact until the coated granules reach at least the ileum and thereafter provide a sustained release of the drug in the colon. Suitable coating materials are selected from the Eudragit range of (meth)acrylate and (meth)acrylic and polymers. The invention has particular application to topically active drugs such as topically active steroids, bismuth salts and complexes, and especially, 5-amino-salicylic acid.

The present invention relates to the administration of drugs to theintestine and has particular, but not exclusive, application to thetreatment of colonic disorders by administration to the ileum and/orcolon of drugs such as 5-amino-salicylic acid (hereinafter referred toas 5-ASA).

Treatment of diseases of the intestine usually requires the delivery ofa drug to the affected site. When the disease is essentially confined toa specific part of the intestine, such as the colon in ulcerativecolitis or Crohn's colitis, it is desirable to target administration ofthe drug to that part in order to provide and control optimum localconcentration of the drug. In this connection, some drugs such as 5-ASAare absorbed or inactivated in the small intestine.

The formulation of a drug in a conventional enteric coated capsule ortablet merely prevents release of the drug until the alkalineenvironment of the small intestine is reached. The problem of targetingthe drug to the colon in an effective and viable manner was not solveduntil the proposal by the present inventors to coat solid oral dosageforms with a thick coating of an anionic polymer of defined pHdissolution profile (see EP-A-0097651).

Several "delayed release" forms of orally administrable drugs have beenproposed. The delayed release may result from the physical properties ofthe formulation or from the chemical and physical properties of aderivative of the drug. It is known to provide capsules and tablets witha coating which will disintegrate to release the drug gradually when thecapsule or tablet has reached the acid environment of the stomach or thealkaline environment of the small intestine. Similarly, it is known toprovide capsules and tablets with a coating permeable to the drugcontained and through which the drug is gradually released.

It was proposed in GB-A-1219026 (published January 1971) to embedindividual particles of a drug in a slowly disintegrating or slowlydissolving resin matrix having a particular dissolution profile toprovide an orally administrable formulation for selectivelyadministering the drug to the large intestine. The resin is selectedsuch that the drug remains substantially protected within the resinmatrix while the particles travel through the stomach and smallintestine of a patient and that the drug is substantially completelyexposed at the time the particles reach the large intestine. Inparticular, the nature and amount of the resin is selected so that whena quantity of the embedded drug is introduced into a Stoll-Gershbergdisintegration apparatus, submerged in a simulated intestinal fluid(made in accordance with the U.S. Pharmacopoeia, Volume XVII, 1965 atpage 919 but modified by containing no pancreatin), and operated asdescribed in the patent specification, 2% to 12% of the drug dissolveswithin an hour of the introduction of the formulation into the fluid and18% to 88% of the drug dissolves within three hours of saidintroduction. It is specifically stated that the resin is selected sothat the dissolution rate of the drug is not pH dependent but is timedependent. The preferred resin is a high-viscosity grade modified vinylacetate resin (available under the Registered Trade Mark "Gelva" C3-V30)and other specified resins are carboxylated polyvinyl acetates,polyvinyl/maleic anhydride copolymers, poly(methacrylic acid),ethylene/maleic anhydride copolymers, ethyl cellulose, methylacrylicacid/methyl methacrylate copolymers, waxes and mixtures thereofincluding mixtures with shellac. Tablets of the embedded particlescoated with a standard coating solution containingcellulose-acetate-phthalate are reported.

It will be appreciated that the carrier system disclosed in GB-A-1219026relies upon the rate of disintegration or dissolution of the resin asthe preparation passes through the gastro-intestinal tract. The timedependency makes it impossible to limit administration of the drug tothe colon because of large variations in the transit time in thegastro-intestinal tract, especially in the stomach, which occur betweendifferent patients and in the same patient from time to time. It wouldappear that the carrier system has not been satisfactory in practicebecause we are not aware of any relevant product presently available inthe UK or elsewhere.

Anionic polymers have been known for many years to be of use in thepreparation of coatings for capsules and to provide delayed or sustainedrelease of an encapsulated drug. In particular, it has been known sinceat least 1974 to use for said coatings anionic copolymers of methacrylicacid and methacrylic acid methyl ester. Such a copolymer (available fromRohm Pharma GmbH, Darmstadt, Germany under the Registered Trade Mark"Eudragit" S) in which the ratio of free carboxyl groups to ester groupsis approximately 1:2 had having a mean molecular weight of 135,000 isknown to be insoluble in gastric juice and poorly soluble in intestinaljuice while an analogous copolymer (available Rohm Pharma GmbH,Darmstadt, Germany under the Registered Trade Mark "Eudragit" L)differing only in so far as said ratio is approximately 1:1 also isinsoluble in gastric juice but is readily soluble in intestinal juice.Prior to the invention of EP-A-0097651, said copolymers were usuallyemployed to provide a coating of between 25 and 40 micrometers thick andthe poorly soluble (in intestinal juice) copolymer usually is employedto reduce the dissolution (in intestinal juice) of the readily solublecopolymer. In general terms, except in connection with the invention ofEP-A-0097651, anionic polymer coatings on oral dosage forms have beenrequired to dissolve in aqueous medium at a pH below 7, usually betweenpH 5.5 and pH 7. Eudragit S dissolves above pH 7 but, as noted above,usually is employed in admixture with Eudragit L. As far as we areaware, said mixtures invariably dissolve below pH 7.

Salicylazosulphapyridine (also known as sulphasalazine or salazopyrinand hereinafter referred to as SASP) consists of sulphapyridine linkedto a salicylate group by a diazo bond and has been used for decades inthe treatment of colitis, Crohn's disease, idiopathic proctitis andchronic arthritis. Orally administered SASP is only absorbed to alimited extent before reaching the colon where azo-reductases producedby colonic bacteria act to split SASP into sulphapyridine and 5-ASA.Studies by A. K. A. Khan et al (The Lancet, Oct. 29 1977, p. 892) andothers have shown the 5-ASA to be the pharmacologically active agent inthe treatment of colonic disease with SASP. Sulphasalazine appearsmerely to act as a chemical carrier to deliver 5-ASA to the colon. Whenadministered orally without the azo-bond joining them, sulphapyridineand 5-ASA are almost entirely absorbed from the small intestine beforereaching the colon.

Several proposals have been made in recent years for the oraladministration of 5-ASA avoiding using SASP in order to reduce theoccurrence of side effects attributable to the sulphapyridine moiety.For example, in U.S. Pat. No. 4,190,716 (published February 1980), itwas proposed to covalently bond the 5-ASA to a nonabsorbablepharmacologically acceptable organic polymer backbone comprising aplurality of aromatic rings by azo bonds bridging aromatic carbon atomsand the 5-position carbon of 5-ASA.

In GB-A-2021409 (published December 1979), it was proposed that 5-ASAshould be administered concurrently or concomitantly with certaindisodium cromoglycate-like compounds. Reference is made to formulating5-ASA in sustained or controlled release form by coating some or all5-ASA particles or granules thereof with a slowly soluble or digestibleor semi-permeable layer of material such as beeswax, Carnauba wax,stearic or palmitic acids or cetyl alcohol. Reference also is made tocoating tablets of the coated or uncoated 5-ASA with a continuous filmof a material such as shellac or cellulose acetate phthalate which isresistant and impermeable to gastric secretions but susceptible tointestinal secretions. None of the coating materials specified orindicated in the specification are such as to prevent release of 5-ASAuntil the colon.

WO-A-81/02671 (published October 1981) proposed formulating 5-ASA in asustained release tablet or enterosoluble tablet form and specifiesethyl cellulose as the preferred coating material. No coating materialsother than cellulose derivatives are mentioned and it is granules, asdistinct from tablets or other solid oral dosage forms, which aredescribed as being coated. The coating is intended to provide sustainedrelease of 5-ASA throughout the small and large intestine.

EP-A-0040590 (published November 1981) proposes coating a core of 5-ASAwith a coating material comprising at least, (a) 10 to 85% by weight ofan anionic carboxylic polymer soluble only above pH 5.5 and (b) 15 to90% by weight of a water-soluble, quaternary ammonium substitutedacrylic polymer. It is stated that the coating normally will be 3 to 60,preferably 10 to 30, micrometers thick and that partly methyl esterifiedmethacrylic acid polymers are suitable anionic carboxylic polymers foruse as component (a). In the Examples, Eudragit L and a mixture ofEudragit L and Eudragit S constitute the component (a) and in all casesthe coatings dissolved below pH 7. The coated bodies of the EP-A-0040590are subsequently included in dosage units which normally contain atleast 10 coated bodies. The rationale of the coating system is stated tobe that the change of pH from acid to neutral at the pylorus triggers achange in the physical condition of the coating so that 5-ASA issubsequently released after a predetermined time lag by which time theformulation should have reached the colon. Although time of passagethrough the small intestine is relatively constant, it still varies from2 to 5 hours and hence the carrier system does not provide for reliablerelease of 5-ASA specifically in the colon.

EP-A-0097651 (published February 1983 as WO-A-8300435) disclosed that5-ASA reliably can be administered specifically to the large intestine,especially the colon, by simply coating a solid oral dosage form with a60 to 150 micrometers thick layer of an anionic polymer which isinsoluble in gastric juice and in intestinal juice below pH 7 butsoluble in colonic intestinal juice, whereby the oral dosage formremains intact until it reaches the colon. This carrier system differsfrom those previously disclosed in relation to 5-ASA in that dissolutionor disintegration does not occur until entry of the coated dosage forminto the colon. In particular, there is substantially no leaching out ofthe 5-ASA downstream of the colon in the normal patient. The carriersystem is not limited to 5-ASA but can be used for other drugs, such asprednisolone methasulphobenzoate, which require to be targeted to thecolon.

Although the 5-ASA formulation of EP-A-0097651 has found widespread andincreasing use in the treatment of ulcerative colitis or Crohn'scolitis, there are occasions upon which it would be desirable to avoidthe release of a large bolus of 5-ASA or other drug in the colon and todeliver the drug in smaller quantities instead to give more of a plateaurelease than the rapid peak absorption caused by bolus releases and toreduce the risk of local irritation. Further, it is desirable to providea more flexible release system which would permit targeted release inthe small intestine instead of in the colon. Accordingly, we haveinvestigated the possibility of alternative formulations for targetingdrugs to the intestine. As a result of those investigations, we havefound that the drug can successfully be targeted by replacing the coatedoral dosage form of EP-A-0097651 with individually coated granuleswithin an enteric coated capsule.

In its broadest aspect, the present invention provides an orallyadministrable pharmaceutical dosage form for selectively administering adrug to the intestine comprising a plurality of granules of the drugcontained in a capsule, characterized in that said granules and saidcapsule are coated with the same or different coating material whichdissolves in the intestine.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows the percent of 5-ASA released from coated granulescomprised of 12%, 16%, 20%, 22% and 25% of the coating mixture when thegranules were exposed to pH 1.2 for 2 hours, then pH 6.4 for 1 hour andfinally pH 7.2 for 1 hour.

According to a preferred embodiment, the present invention provides anorally administrable pharmaceutical dosage form for selectivelyadministering a drug to the large intestine comprising a plurality ofgranules of the drug contained in an enterically coated capsule whichreleases the granules in the small intestine, characterized in that saidgranules are coated with a coating which remains substantially intactuntil the coated granules reach at least the ileum and, preferably,thereafter provides a sustained release of the drug in the colon.

According to an especially preferred embodiment of the presentinvention, there is provided an orally administrable pharmaceuticaldosage form for selectively administering a drug to the colon comprisinga plurality of granules of the drug contained in an enterically coatedcapsule which releases the granules in the small intestine,characterized in that said granules are coated with a coating materialcomprising an anionic polymer which is insoluble in gastric juice and inintestinal juice below pH 7 but is soluble in colonic intestinal juicewhereby the coating on the released coated granules remainssubstantially intact until the granules reach at least the ileum and,preferably, thereafter provides a sustained release of the drug in thecolon.

Although the invention has particular application to 5-ASA, it can beused to target any desired drug, especially a topically active drug, tothe intestine. In particular, it has application to the administrationof topically active steroids such as prednisolone metasulphobenzoate tothe ileum and/or colon. Other drugs which can be administered by theinvention include bismuth salts or complexes, for examplebismuth-carboner complexes. The relevant drug will be present in thedosage form of the invention in suitable unit dose amounts. Said amountswill be known or readily ascertainable by those skilled in the art. Inmany cases, said amounts are likely to be less than those presentlyadministered by conventional delayed or sustained release dosage formsbecause of the high organ specificity of the dosage form of the presentinvention.

The drug is present in the dosage form of the invention in granularform. Suitably the granules are 0.25 to 4 mm, usually 0.25 to 2.5 mm,especially 0.4 to 1.5 mm and particularly about 0.6 mm, diameter.

The coating can be applied to the granules by any suitable known coatingtechnique. In particular, conventional coating techniques such as sprayor pan coating can be employed. (See, eg, "Film coatings on acrylicresin basis for dosage forms with controlled drug release" PharmaInternational 1/2 (1975) 3.) Preferably, the coating is applied fromaqueous suspension.

The granular coating material can be any suitable coating, e.g.cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate,ethyl cellulose or polyvinyl acetate phthalate but the preferred coatingmaterial is an anionic polymer, especially one having the dissolutionprofile specified in EP-A-0097651, optionally in admixture with aneutral insoluble but permeable polymer. The presently preferred anionicpolymers are anionic carboxylic polymers, i.e. polymers in which theanionic groups are at least predominantly free carboxylic and/oresterified carboxylic groups. It is particularly preferred that theanion polymers should be acrylic polymers and the presently mostpreferred polymers are partly methyl esterified methacrylic acidpolymers in which the ratio of free acid groups to ester groups is about1:1 (i.e. Eudragit L), or especially, about 1:2 (i.e. Eudragit S). Theneutral insoluble but permeable polymers preferably are acrylic esterpolymers, especially methylmethacrylate ester copolymers withethylacrylate. Suitably, the molecular ratio of anionic polymer toneutral polymer is in the range 5:1 to 1:5, especially 3:1 to 1:3, mostpreferably 1:1 to 1:3.

The thickness of coating required on the granules will depend upon thedissolution profile of the particular coating materials and possiblyalso upon the dissolution profile of the enteric coating on the capsule.However, it is well within the ability of the man of average skill inthe art to determine by trial-and-error experimentation the optimumthickness of a particular coating required for a particular dosage formof the invention. When using an aqueous dispersion of a partly methylesterified methacrylic acid polymer of the Eudragit S type admixed witha methylmethacrylate/ethylacrylate copolymer, the amount of coatingmaterial usually will be between 15 and 30% dry weight based on theuncoated granule) with 20 to 25% being preferred.

The coating can, and usually will, contain plasticiser and possiblyother coating additives such as colouring agents, gloss producers, talcand/or magnesium stearate as well known in the coating art. Inparticular, anionic carboxylic acrylic polymers usually contain 10 to25% by weight of a plasticiser especially diethyl phthalate, althoughthe presence of such a plasticiser may not be necessary when using anaqueous suspension for coating.

Usually, the capsule into which the coated granules are loaded will be asoft or, preferably, hard gelatin capsule although other capsules whichwill dissolve in the small intestine can be used. The capsule is coatedwith an enteric coating which will protect it during passage through thestomach. Any conventional enteric coating material which is soluble inthe small intestine can be used, e.g. cellulose acetate phthalate,hydroxy propylmethyl cellulose phthalate or initially ethyl cellulosefollowed by polyvinyl acetate phthalate, but it is preferred to use ananionic polymer having an appropriate dissolution profile. The presentlypreferred polymers are anionic carboxylic polymers, i.e. polymers inwhich the anionic groups are at least predominantly free carboxylicand/or esterified carboxylic groups. It is particularly preferred thatthe polymers should be acrylic polymers and the presently most preferredpolymers are partly methyl esterified methacrylic acid polymers in whichthe ratio of free acid groups to ester groups is about 1:1 (i.e.Eudragit L).

The enteric coating can, and usually will contain plasticiser andpossibly other coating additives such as colouring agents, glossproducers, talc and/or magnesium stearate as well known in the coatingart. In particular, anionic carboxylic acrylic polymers usually contain10 to 25% by weight of a plasticiser especially diethyl phthalate.

Conventional coating techniques such as spray or pan coating areemployed to apply the enteric coating (See for example D. Dreher "Filmcoatings on acrylic resin basis for dosage forms with controlled drugrelease" Pharma International 1/2 (1975) 3.)

The following non-limiting Examples are provided to illustrate thedosage forms of the invention:

EXAMPLE 1

Granules of size in the range 0.5-2.1 mm were prepared by dry compactingand subsequently sieving a tablet mass containing 5-ASA. The granuleswere then spray coated with an aqueous suspension to provide a 20% or25% dry weight gain based on uncoated granule weight of a mixture ofEudragit S100 and Eudragit NE 30 D (Rohm Pharma GmbH, Darmstadt,Germany) in the ratio of 3:7. Eudragit S100 is a copolymer ofmethacrylic acid and methylmethacrylate in the ratio of 1:2 in powderform and Eudragit NE 30 D is a 30% aqueous dispersion of a copolymer ofethylacrylate and methylmethacrylate in the ratio 2:1.

The resulting granules had the following formulations:

    ______________________________________                                        Material         20% coating                                                                              25% coating                                       ______________________________________                                        5-ASA            59.1 g     55.8 g                                            Lactose          11.3 g     10.7 g                                            Povidone (ie. PVP)                                                                             1.3 g      1.2 g                                             Explotab (Na starch                                                                            2.7 g      2.5 g                                             glycolate)                                                                    Mg stearate      0.9 g      0.9 g                                             Talc             9.2 g      10.6 g                                            Eudragit S100    4.6 g      5.4 g                                             Eudragit NE 30 D 10.8 g     12.7 g                                            Antifoam emulsion SE 2                                                                         0.1 g      0.1 g                                             Total            100.0 g    100.0 g                                           ______________________________________                                    

Each of the batches of coated granules were separately packed into size00 hard gelatin capsules (LOK-CAP, Eli Lilly) in an amount of 400 mggranules per capsule. The capsules were then spray coated with 150 mlper capsule of a coating solution of the following formula:

    ______________________________________                                        Eudragill L powder   3       g                                                Diethyl phthalate    0.75    ml                                               Silicone fluid 200 cs                                                                              0.75    ml                                               Acetone              to 100  ml.                                              ______________________________________                                    

Seven healthy volunteers were then each given blind on three separateoccasions a single dose consisting of (a) 8 tablets of enteric coated500 mg sulphasalazine tablets, (b) 8 of the enteric coated capsulescontaining the 20% Eudragit coated 5-ASA granules, and (c) 8 of theenteric coated capsules containing the 25% Eudragit coated 5-ASAgranules. The serum levels of 5-ASA and N-acetyl-5-ASA at various timesfollowing administration were measured together with the total urinaryexcretion of 5-ASA and N-acetyl-5-ASA. The mean of the values recordedare set forth in the following Tables 1 to 3. In each case the valuesare given to three significant figures with 0 representing less than 2ng/ml. The following abbreviations are used:

T_(max) =time for the maximum serum concentration in hours, median andinterquartials ranges

C_(max) =maximum serum concentration attained in ng/ml

AUC=area under the serum concentration time curve (50 h; ng.h/ml)

T_(half) =estimated biological half life of elimination

KE=estimated first order in elimination rate constant

                  TABLE 1                                                         ______________________________________                                        Mean serum levels of 5-ASA (ng/ml) in 7 volunteers                            following administration of the three different drug                          formulations.                                                                 Time (h)                                                                             5-ASA 20%    Sulphasalazine                                                                            5-ASA 25%                                     ______________________________________                                         0     0 ± 0     0 ± 0    0 ± 0                                       2     9 ± 7     0 ± 0    1 ± 0                                       3.5   102 ± 88  0 ± 0    70 ± 40                                     5     227 ± 142 7 ± 4    155 ± 65                                    6.5   153 ± 101 30 ± 19  54 ± 22                                     8     193 ± 108 30 ± 15  73 ± 37                                     9.5   143 ± 104 49 ± 19  37 ± 15                                    12     17 ± 7    61 ± 29  17 ± 9                                     15     38 ± 23   99 ± 31  22 ± 15                                    26     56 ± 28   43 ± 23  4 ± 3                                      36     19 ± 10   12 ± 9   10 ± 10                                    50     6 ± 4     1 ±  1   14 ± 14                                    T.sub.max                                                                            6.5 (3.1-13.6)                                                                             15 (6.5-15) 5 (3.8-6.9)                                   C.sub.max                                                                            400 ± 142 102 ± 32 215 ± 54                                   AUC    2480 ± 450                                                                              1610 ± 664                                                                             1080 ± 299                                 T.sub.half                                                                           7.2 ± 3.0 19.4 ± 12.9                                                                            1.7 ± 0.6                                  KE     0.2 ± 0.1  0.1 ± 0.04                                                                            0.7 ± 0.3                                  ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Mean serum levels of N-Ac-5-ASA (ng/ml) in 7                                  volunteers following administration of the three                              different drug formulations.                                                  Time (h)                                                                             5-ASA 20%    Sulphasalazine                                                                            5-ASA 25%                                     ______________________________________                                         0     0 ± 0     0 ± 0    0 ± 0                                       2     90 ± 53   0 ± 0    9 ± 9                                       3.5   363 ± 267 18 ± 17  258 ± 113                                   5     756 ± 388 97 ± 52  473 ± 174                                   6.5   714 ± 280 186 ± 84 410 ± 93                                    8     650 ± 228 343 ± 134                                                                              453 ± 77                                    9.5   545 ± 205 391 ± 117                                                                              436 ± 69                                   12     417 ± 119 556 ± 88 440 ± 151                                  15     425 ± 184 763 ± 151                                                                              355 ± 86                                   26     590 ± 124 505 ± 130                                                                              182 ± 40                                   36     389 ± 140 285 ± 117                                                                              169 ± 72                                   50     188 ±  92 191 ± 133                                                                              125 ± 92                                   T.sub.max                                                                            26 (6.1-26)  15 (13.3-17.8)                                                                            8 (5-9.5)                                     C.sub.max                                                                            1420 ± 296                                                                              841 ± 153                                                                              822 ± 112                                  AUC    21300 ± 2270                                                                            18400 ± 3820                                                                           11800 ± 2090                               T.sub.half                                                                           10.8 ± 2.4                                                                              60.1 ± 50.1                                                                            12.8 ± 4.5                                 KE      0.1 ± 0.02                                                                              0.1 ± 0.02                                                                             0.1 ± 0.01                                ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        Mean urinary excretion of 5-ASA and N-Ac-5-ASA (ng/ml)                        in 7 volunteers following administration of the three                         different drug formulations.                                                           5-ASA 20%   Sulphasalazine                                                                            5-ASA 25%                                    ______________________________________                                        5-ASA    5.35 ± 2.59                                                                            0 ± 0    1.40 ± 0.35                               N-AC-5-ASA                                                                             194 ± 24 170 ± 35 129 ± 29                                  ______________________________________                                    

As can be seen from the tables, the mean serum concentrations of 5-ASAwere lower than those of its acetylated metabolite following oralingestion of each of the three preparations. Peak concentrations ofserum 5-ASA and N-acetyl-5-ASA occurred earlier with both 5-ASA capsulescompared with sulphasalazine. However, following administration of thecapsule containing 20% Eudragit coated 5-ASA there was a second rise inboth serum 5-ASA and N-acetyl-5-ASA at 15 h, with levels thereaftersimilar to those after sulphasalazine.

These results suggest that more 5-ASA is available for earlierabsorption after ingestion of the 5-ASA capsules than aftersulphasalazine. The early peaks after both capsules correspond to drugabsorbed in the small bowel following dissolution of the capsule coatedwith Eudragit-L. Other granules reach the terminal ileum and proximalcolon where, at a pH above 7, further drug release would be expected.This accounts for the second rises of serum 5-ASA and N-acetyl-5-ASAseen 15 hours after ingestion of the capsule containing 20% Eudragitcoated 5-ASA.

Release of free 5-ASA in the proximal small bowel, or substantialrelease of the drug in one region of the ileal or ileo-caecal area, canlead to high peak serum levels of 5-ASA and its metabolites, leavingless drug available for topical action in the colon. The coatedgranules/coated capsules of this invention deliver 5-ASA to the distalsmall bowel, limit sudden release of free compound, and make the drugavailable for absorption over a longer period as with sulphasalazine.

EXAMPLE 2

The granule coating procedure of Example 1 was repeated using 12%, 16%,20%, 22% and 25% of the coating mixture. The dissolution of the coatedgranules was examined by a standard flow-through cell dissolution systemwhich automatically changed the pH at pre-determined time intervals. Thecoated granules were exposed to pH 1.2 for 2 h, then pH 6.4 for 1 h, andfinally pH 7.2 for 1 h. 5-ASA was measured spectrophotometrically andthe results are shown in FIG. 1.

As can be seen, the pH influenced the drug release from granules coatedwith at least 16% dry lacquer substance.

With 20% of dry lacquer substance, the amount of 5-ASA release after 2 hat pH 1.2 was 7.8%, compared with 18.5% at pH 6.4 for 1 h, and 77.8%after 1 h at pH 7.2 (accumulated percentages); with 25% of dry lacquersubstance the respective percentage 5-ASA release was 3.6%, 10% and 48%.

We claim:
 1. An orally administrable pharmaceutical dosage form forselectively administering a drug to the intestine comprising a pluralityof granules of the drug contained in an enterically coated capsule whichreleases the granules in the small intestine, wherein said granules arecoated with a coating which remains substantially intact until thecoated granules reach at least the ileum.
 2. An orally administrablepharmaceutical dosage form for selectively administering a drug to theintestine comprising a plurality of granules of the drug contained in anenterically coated capsule which releases the granules in the smallintestine, wherein said granules are coated with a coating comprising ananionic polymer which is insoluble in gastric juice and in intestinaljuice below pH 7 but is soluble in colonic intestinal juice whereby thecoating on the released coated granules remains substantially intactuntil the granules reach at least the ileum.
 3. An orally administrablepharmaceutical dosage form for selectively administering a drug to theintestine comprising a plurality of granules of the drug contained in acapsule coated with a coating comprises a partly methyl esterifiedmethacrylic acid polymer having a ratio of free acid groups to estergroups of about 1:1 whereby the granules are released in the smallintestine, wherein said granules are coated with a coating comprising apartly methyl esterified methacrylic acid polymer having a ratio of freeacid groups to ester groups of about 1:2 and which is insoluble ingastric juice and in intestinal juice below pH 7 but is soluble incolonic intestinal juice whereby the coating on the released coatedgranules remains substantially intact until the granules reach at leastthe ileum.
 4. An orally administrable pharmaceutical dosage form forselectively administering a drug, selected from the group consisting of5-aminosalicylic acid and a pharmaceutically acceptable salt or esterthereof; topically active steroids; and bismuth salts and complexes, tothe intestine comprising a plurality of granules of the drug containedin an enterically coated capsule which releases the granules in thesmall intestine, wherein said granules are coated with a coating whichremains substantially intact until the coated granules reach at leastthe ileum.
 5. An orally administrable pharmaceutical dosage form forselectively administering a drug, selected from the group consisting of5-aminosalicylic acid and a pharmaceutically acceptable salt or esterthereof; topically active steroids; and bismuth salts and complexes, tothe intestine comprising a plurality of granules of the drug containedin an enterically coated capsule which releases the granules in thesmall intestine, wherein said granules are coated with a coatingcomprising an anionic polymer which is insoluble in gastric juice and inintestinal juice below pH 7 but is soluble in colonic intestinal juicewhereby the coating on the released coated granules remainssubstantially intact until the granules reach at least the ileum.
 6. Anorally administrable pharmaceutical dosage form for selectivelyadministering a drug, selected from the group consisting of5-aminosalicylic acid and a pharmaceutically acceptable salt or esterthereof; topically active steroids; and bismuth salts and complexes, tothe intestine comprising a plurality of granules of the drug containedin a capsule coated with a coating comprises a partly methyl esterifiedmethacrylic acid polymer having a ratio of free acid groups to estergroups of about 1:1 whereby the granules are released in the smallintestine, wherein said graules are coated with a coating comprising apartly methyl esterified methacrylic acid polymer having a ratio of freeacid groups to ester groups of about 1:2 and which is insoluble ingastric juice and in intestinal juice below pH 7 but is soluble incolonic intestinal juice whereby the coating on the released coatedgranules remains substantially intact until the granules reach at leastthe ileum.
 7. A dosage form as claimed in claim 1, wherein said, granulecoating provides a sustained release of the drug in the colon.
 8. Adosage form as claimed in claim 2, wherein said granule coating providesa sustained release of the drug in the colon.
 9. A dosage form asclaimed in claim 1, wherein said drug is 5-aminosalicylic acid or apharmaceutically acceptable salt or ester thereof.
 10. A dosage form asclaimed in claim 1, wherein the drug is a topically active steroid or abismuth salt or complex.
 11. A dosage form as claimed in claim 2,wherein the anionic polymer is a partly methyl esterified methacrylicacid polymer.
 12. A dosage form as claimed in claim 11, wherein thepartly methyl esterified methacrylic acid polymer has a ratio of freeacid groups to ester groups of about 1:2.
 13. A dosage form as claimedin claim 1, wherein the capsule is a hard gelatin capsule.
 14. A dosageform as claimed in claim 1, wherein the capsule is coated with ananionic carboxylic acrylic polymer.
 15. A dosage form as claimed inclaim 14, wherein the capsule coating is a partly methyl esterifiedmethacrylic acid polymer.
 16. A dosage form as claimed in claim 15,wherein the capsule coating is a partly methyl esterified methacrylicacid polymer having a ratio of free acid groups to ester groups of about1:1
 17. A method of treating ulcerative colitis or Crohn's diseasecomprising orally administering to a person suffering therefrom apharmaceutically effective amount for the treatment of ulcerativecolitis or Crohn's disease of a drug selected from the group consistingof 5-aminosalicylic acid and a pharmaceutically acceptable salt or esterthereof; topically active steroids; and bismuth salts and complexes, inan pharmaceutical dosage form comprising a plurality of granules of thedrug contained in an enterically coated capsule which releases thegranules in the small intestine, wherein said granules are coated with acoating which remains substantially intact until the coated granulesreach at least the ileum.
 18. A method of treating ulcerative colitis orCrohn's disease comprising orally administering to a person sufferingtherefrom a pharmaceutically effective amount for the treatment ofulcerative colitis or Crohn's disease of a drug selected from the groupconsisting of 5-aminosalicylic acid and a pharmaceutically acceptablesalt or ester thereof; topically active steroids; and bismuth salts andcomplexes, in a pharmaceutical dosage form comprising a plurality ofgranules of the drug contained in an enterically coated capsule whichreleases the granules in the small intestine, wherein said granules arecoated with a coating comprising an anionic polymer which is insolublein gastric juice and in intestinal juice below pH 7 but is soluble incolonic intestinal juice whereby the coating on the released coatedgranules remains substantially intact until the granules reach at leastthe ileum.
 19. A method of treating ulcerative colitis or Crohn'sdisease comprising orally administering to a person suffering therefroma pharmaceutically effective amount for the treatment of ulcerativecolitis or Crohn's disease of a drug selected from the group consistingof 5-aminosalicylic acid and a pharmaceutically acceptable salt or esterthereof; topically active steroids; and bismuth salts and complexes, ina pharmaceutical dosage form comprising a plurality of granules of thedrug contained in a capsule coated with a coating comprises a partlymethyl esterified methacrylic acid polymer having a ratio of free acidgroups to ester groups of about 1:1 whereby the granules are released inthe small intestine, wherein said granules are coated with a coatingcomprising a partly methyl esterified methacrylic acid polymer having aratio of free acid groups to ester groups of about 1:2 and which isinsoluble in gastric juice and in intestinal juice below pH 7 but issoluble in colonic intestinal juice whereby the coating on the releasedcoated granules remains substantially intact until the granules reach atleast the ileum.